Genetic factors govern the susceptibility of individuals to a variety of human autoimmune diseases. The role of genetic factors in MS is significant. Polygenic inheritance likely characterizes MS, and it has been estimated that 1 to 3 susceptibility loci would predict the different rates of MS occurrence in studied populations. It is important to understand the nature and impact of the genes critical for susceptibility in MS, but this is problematic in any polygenic human disease, given the low general incidence, the low number of multiplex families, the small size of informative families and in the genetic diversity of the human population. Dissection of these traits in animal models is much more feasible because inbred strains may be used to control for genetic heterogeneity and even polygenic phenotypes can be understood at the genetic level. While it is not a perfect model, the genetic loci that have been found to be important in susceptibility to autoimmunity in animal models are proving useful in identifying relevant genes or pathways that are generalizable to the human conditions for which etiologic agents are unknown. We study the mechanisms and genetic control of EAE-susceptibility in inbred rats, with the goal of elucidating why certain rat strains show relatively strong resistance to the induction of this animal model of human multiple sclerosis. The ultimate goal of our research is to shed light on the genetic control autoimmunity, with possible extension to understanding the mechanisms of heritability of MS. We have now identified genetic markers that are useful for genomic screening of EAE-informative rat strain combinations and have performed the necessary preliminary genome exclusion mapping. We now propose to identify and physically map two EAE-modifying (Eaem) genes in relevant segments of rat chromosomes 4 and 5. Our results have shown that at least one gene is responsible for the EAE-susceptibility difference between F344 EAE-resistant and LEW EAE-susceptible rats; and three genes distinguish LER EAE-resistant rat from LEW rats for this trait. Our results show substantial support for the hypothesis that genes linked to the T cell receptor beta chain complex play a significant role in resistance to this autoimmune disease. In the next support period we propose to extend our genome exclusion mapping results to identify other Eae-m loci, to isolate the chromosomal segments containing these susceptibility loci in congenics, and to test the congenics for the presence of one hallmark characteristic of EAE-(MS-) susceptibility: the polarization of myelin-responsive T cells to the encephalitogenic Th1 phenotype.